Cancer Research-UK Stromal-Tumor Interaction Group, Paterson Institute for Cancer Research, The University of Manchester, Manchester M20 4BX, United Kingdom.
Proc Natl Acad Sci U S A. 2010 Nov 16;107(46):20009-14. doi: 10.1073/pnas.1013805107. Epub 2010 Nov 1.
Much interest is currently focused on the emerging role of tumor-stroma interactions essential for supporting tumor progression. Carcinoma-associated fibroblasts (CAFs), frequently present in the stroma of human breast carcinomas, include a large number of myofibroblasts, a hallmark of activated fibroblasts. These fibroblasts have an ability to substantially promote tumorigenesis. However, the precise cellular origins of CAFs and the molecular mechanisms by which these cells evolve into tumor-promoting myofibroblasts remain unclear. Using a coimplantation breast tumor xenograft model, we show that resident human mammary fibroblasts progressively convert into CAF myofibroblasts during the course of tumor progression. These cells increasingly acquire two autocrine signaling loops, mediated by TGF-β and SDF-1 cytokines, which both act in autostimulatory and cross-communicating fashions. These autocrine-signaling loops initiate and maintain the differentiation of fibroblasts into myofibroblasts and the concurrent tumor-promoting phenotype. Collectively, these findings indicate that the establishment of the self-sustaining TGF-β and SDF-1 autocrine signaling gives rise to tumor-promoting CAF myofibroblasts during tumor progression. This autocrine-signaling mechanism may prove to be an attractive therapeutic target to block the evolution of tumor-promoting CAFs.
目前,人们对肿瘤基质相互作用的新兴作用非常关注,这些作用对于支持肿瘤进展至关重要。癌相关成纤维细胞(CAF)经常存在于人类乳腺癌的基质中,其中包括大量的肌成纤维细胞,这是激活成纤维细胞的标志。这些成纤维细胞具有显著促进肿瘤发生的能力。然而,CAF 的精确细胞起源以及这些细胞演变成促进肿瘤的肌成纤维细胞的分子机制仍不清楚。通过共植入乳腺肿瘤异种移植模型,我们表明在肿瘤进展过程中,常驻的人乳腺成纤维细胞逐渐转化为 CAF 肌成纤维细胞。这些细胞越来越多地获得两种自分泌信号环路,由 TGF-β 和 SDF-1 细胞因子介导,它们都以自刺激和交叉通讯的方式发挥作用。这些自分泌信号环路启动并维持成纤维细胞向肌成纤维细胞的分化以及同时发生的促进肿瘤的表型。总之,这些发现表明,自我维持的 TGF-β 和 SDF-1 自分泌信号的建立导致了肿瘤促进性 CAF 肌成纤维细胞在肿瘤进展过程中的产生。这种自分泌信号机制可能被证明是阻止促进肿瘤的 CAF 演变的有吸引力的治疗靶点。